The present invention relates to low density (less than about 1 g/ml) oral pharmaceutical compositions in unit dosage form suitable for swallowing comprising a soluble bismuth-containing pharmaceutical agent, preferably a soluble bismuth-containing pharmaceutically-acceptable salt suitable for oral co-administration of bismuth and an H.sub.2 receptor blocking anti-secretory agent, with said salts comprising bismuth, an organic acid, and an H.sub.2 receptor blocking anti-secretory agent (preferably selected from the group consisting of ranitidine or cimetidine).
Soluble bismuth-containing pharmaceutical agents are known. Colloidal bismuth subcitrate is described, for example, in European Patent 0,075,992, U.S. Pat. No. 4,801,608, and Great Britain Patent 1,478,742. Pharmaceutically-acceptable salts suitable for oral co-administration of bismuth and an H.sub.2 receptor blocking anti-secretory agent are described in European Patent Application Publication No. 282,132. Furthermore, such salts comprising ranitidine are also described in Great Britain Patent Application Publication No. 2,220,937.
It has been reported that the highly water soluble bismuth-containing agent colloidal bismuth subcitrate ("CBS"), when dosed as a swallowable tablet, produces a transient sharp peak of bismuth blood level in humans after ingestion (see C. U. Nwokolo et al., Aliment. Pharmacol. Therap., 3, 1989, 29-39). It has been discovered that this tablet form of CBS (which has a density greater than 1 g/ml), in vitro in a liquid acidic medium, has a tendency to sink to the bottom of the liquid and dissolve by first forming liquid CBS solution rather than the desired insoluble bismuth precipitate. It has also been discovered that, by contrast, unit dosage forms which are less dense than this tablet form and also less dense than the acidic medium (about 1 g/ml) do not form this initial CBS liquid but rather quickly forms the desired insoluble bismuth precipitate. Interestingly, when these low density unit dosage forms are weighted to the bottom of the test liquid, again the CBS initially liquifies. In vivo testing confirms that in fact these low density unit dosage forms substantially reduce bismuth blood levels as predicted by these different in vitro characteristics. On the other hand, bismuth subsalicylate which is essentially insoluble in water does not behave similarly.
Therefore, the oral dosage units of the present invention comprising soluble bismuth-containing phrmaceutical agents and having low packing density surprisingly give peak bismuth plasma levels and a total bismuth absorption which are lower than that of denser dosage units. This is contrary to what one might expect--that less dense and thereby more dispersible material would lead to more rapid dissolution and consequently to greater absorption than compressing to higher density the same material. It is also contrary to the current tendency in the art of pharmaceutical production, which is to concentrate the oral dosage units, e.g. by compressing the contents of oral capsules to a high density (see Hard Capsules, Development and Technology, Ed. K. Ridgway 1987, chapter 9, G. C. Cole, pp. 92-103).
An object of the present invention therefore is to provide an oral dosage unit suitable for swallowing which minimizes bismuth absorption comprising a soluble bismuth-containing pharmaceutical agent. Preferred soluble bismuth-containing pharmaceutical agents are colloidal bismuth subcitrate and pharmaceutically-acceptable salts suitable for oral co-administration of bismuth and an H.sub.2 -receptor blocking anti-secretory agent.
This and other objects of the present invention will become readily apparent from the detailed description which follows.
All percentages and ratios used herein are by weight, and all measurements made at 25.degree. C., unless otherwise specified.